Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros

Base de dados
Tipo de documento
Assunto da revista
País de afiliação
Intervalo de ano de publicação
1.
Bioorg Chem ; 136: 106528, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37054528

RESUMO

Intense synthetic efforts have been directed towards the development of noncalcemic analogs of 1,25-dihydroxyvitamin D3. We describe here the structural analysis and biological evaluation of two derivatives of 1,25-dihydroxyvitamin D3 with modifications limited to the replacement of the 25-hydroxyl group by a 25-amino or 25-nitro groups. Both compounds are agonists of the vitamin D receptor. They mediate biological effects similar to 1,25-dihydroxyvitamin D3, the 25-amino derivative being the most potent one while being less calcemic than 1,25-dihydroxyvitamin D3. The in vivo properties of the compounds make them of potential therapeutic value.


Assuntos
Receptores de Calcitriol , Vitamina D , Vitamina D/farmacologia , Calcitriol/química , Calcitriol/farmacologia
2.
J Med Chem ; 67(12): 10386-10400, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38858308

RESUMO

We synthesized two new gemini analogues, UG-480 and UG-481, that incorporate a modified longer side chain containing a cyclopropane group. The evaluation of the bioactivities of the two gemini analogues indicated that the 17,20 threo (20S) compound, UG-480, is the most active one and is as active as 1,25(OH)2D3. Docking and molecular dynamics (MD) data showed that the compounds bind efficiently to vitamin D receptor (VDR) with UG-480 to form an energetically more favorable interaction with His397. Structural analysis indicated that whereas the UG-480 compound efficiently stabilizes the active VDR conformation, it induces conformational changes in the H6-H7 VDR region that are greater than those induced by the parental Gemini and that this is due to the occupancy of the secondary channel by its modified side chain.


Assuntos
Ciclopropanos , Desenho de Fármacos , Receptores de Calcitriol , Ciclopropanos/química , Ciclopropanos/síntese química , Ciclopropanos/farmacologia , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/agonistas , Humanos , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular
3.
ACS Cent Sci ; 10(5): 956-968, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38799662

RESUMO

We report a blueprint for the rational design of G protein coupled receptor (GPCR) ligands with a tailored functional response. The present study discloses the structure-based design of cannabinoid receptor type 2 (CB2R) selective inverse agonists (S)-1 and (R)-1, which were derived from privileged agonist HU-308 by introduction of a phenyl group at the gem-dimethylheptyl side chain. Epimer (R)-1 exhibits high affinity for CB2R with Kd = 39.1 nM and serves as a platform for the synthesis of a wide variety of probes. Notably, for the first time these fluorescent probes retain their inverse agonist functionality, high affinity, and selectivity for CB2R independent of linker and fluorophore substitution. Ligands (S)-1, (R)-1, and their derivatives act as inverse agonists in CB2R-mediated cAMP as well as G protein recruitment assays and do not trigger ß-arrestin-receptor association. Furthermore, no receptor activation was detected in live cell ERK1/2 phosphorylation and Ca2+-release assays. Confocal fluorescence imaging experiments with (R)-7 (Alexa488) and (R)-9 (Alexa647) probes employing BV-2 microglial cells visualized CB2R expressed at endogenous levels. Finally, molecular dynamics simulations corroborate the initial docking data in which inverse agonists restrict movement of toggle switch Trp2586.48 and thereby stabilize CB2R in its inactive state.

4.
ACS Omega ; 5(40): 26049-26055, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33073131

RESUMO

An unexpected ring expansion that converts hydrindanes into decalins via an unprecedented dyotropic reaction involving a mesylate group has been observed, and this paved the way for easy access to polyfunctionalized chiral decalins. These polyfunctionalized chiral decalins can be very useful building blocks for the synthesis of the thia analogues of many natural compounds. They can also be used in asymmetric catalysis and also in the synthesis of the new analogues of vitamin D with a modified D ring and side chain. The use of chiral sulfoxide ligands for asymmetric catalysis or asymmetric sulfur ylide-mediated epoxidation of carbonyl compounds is a very important topic in the field of organic chemistry, hence our results could be useful to the scientific community.

SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa